Alzheimer's disease is a neurodegenerative disorder of which the main symptom is dementia. In Alzheimer's disease patients, atrophy of the cerebral cortex is found and pathologically, the characteristic lesions including senile plaques, changes in neurofibrillary tangles, etc. are observed, in addition to severe loss of nerve cells. Among them, the pathological change observed from a relatively early stage is the formation of senile plaques and since a major component in the senile plaques is amyloid β protein (Aβ), it is considered that abnormalities in the formation or degradation of AD would be closely associated with the onset/progression of Alzheimer's disease. Aβ is cleaved with and produced from the Aβ precursor protein (βAPP) by β-secretase (Science, 286, 735-741, 1999) and γ-secretase, which belong to aspartic proteases. With regard to γ-secretase, it has been revealed that a familial Alzheimer's disease (FAD)-pathogenic gene, presenilin or a presenilin-containing complex takes part in expressing the activity (Nature, 398, 513-517, 1999; Nature, 405, 689-694, 2000).
This Aβ is steadily synthesized/secreted in vivo and it is considered that under normal conditions Aβ will be rapidly degraded but not accumulated. When this degradability decreases for some reason, it results in accumulation of Aβ and conversely when the degradability is enhanced, the accumulation of Aβ can be prevented. Recently, it was clarified that the major enzyme involved in the degradation of Aβ is a neutral endopeptidase, neprilysin (Nature Med., 6, 143-151, 2000). In neprilysin knockout mice, the Aβ level elevated in the brain and the elevation was most remarkable in the hippocampus (Science, 292, 1550-1552, 2001). It was further clarified that the expression of neprilysin declined in the brain of Alzheimer's disease patients (Neuroscience Lett., 297, 97-100, 2001).
It is considered that when the activity or expression of neprilysin enhances to increase degradability of Aβ, clearance of Aβ in the brain will increase to downregulate the accumulation of Aβ. However, the mechanism concerning the downregulation of neprilysin expression is not very clear. Neprilysin is a neutral endopeptidase and has an action of degrading various peptides in the brain. Since a number of physiologically active peptides are present in the brain, there is a possibility that a peptide regulating the expression of neprilysin mediated by GPCR (G-protein coupled receptor) as a receptor or by a nuclear receptor would be present among them. Once the peptide in the brain which regulates the expression of neprilysin can be found, a method of searching a novel drug promoting Aβ degradation can be provided and furthermore, application to novel pharmaceuticals such as therapeutic or preventive agents for Alzheimer's disease, etc. can be provided.